title: DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking.
abstract: Disrupted-In-Schizophrenia 1 (DISC1) is a candidate risk factor for schizophrenia, bipolar disorder and severe recurrent depression. Here, we demonstrate that DISC1 associates robustly with trafficking-protein-Kinesin-binding-1 which is, in turn, known to interact with the outer mitochondrial membrane proteins Miro1/2, linking mitochondria to the kinesin motor for microtubule-based subcellular trafficking. DISC1 also associates with Miro1 and is thus a component of functional mitochondrial transport complexes. Consistent with these observations, in neuronal axons DISC1 promotes specifically anterograde mitochondrial transport. DISC1 thus participates directly in mitochondrial trafficking, which is essential for neural development and neurotransmission. Any factor affecting mitochondrial DISC1 function is hence likely to have deleterious consequences for the brain, potentially contributing to increased risk of psychiatric illness. Intriguingly, therefore, a rare putatively causal human DISC1 sequence variant, 37W, impairs the ability of DISC1 to promote anterograde mitochondrial transport. This is likely related to a number of mitochondrial abnormalities induced by expression of DISC1-37W, which redistributes mitochondrial DISC1 and enhances kinesin mitochondrial association, while also altering protein interactions within the mitochondrial transport complex.
authors.affiliation: University of Edinburgh Centre for Genomics and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, Crewe Road, Edinburgh EH4 2XU, UK and.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ogawa
authors.forename: Elise L V
authors.initials: EL
authors.lastname: Malavasi
authors.forename: Darragh K
authors.initials: DK
authors.lastname: Crummie
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Eykelenboom
authors.forename: Dinesh C
authors.initials: DC
authors.lastname: Soares
authors.forename: Shaun
authors.initials: S
authors.lastname: Mackie
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: J Kirsty
authors.initials: JK
authors.lastname: Millar
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D001523:Mental Disorders / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C412476:DISC1 protein, human; C488101:KIF5B protein, human; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; C531552:TRAK1 protein, human; C473124:RHOT1 protein, human; D016547:Kinesins; D020741:rho GTP-Binding Proteins